イメグリミンによるインクレチン分泌促進作用

概要

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PDF issue: 2024-05-02

Stimulatory effect of imeglimin on incretin
secretion

権, 映月
(Degree)
博士（医学）

(Date of Degree)
2023-03-25

(Resource Type)
doctoral thesis

(Report Number)
甲第8691号

(URL)
https://hdl.handle.net/20.500.14094/0100485875
※ 当コンテンツは神戸大学の学術成果です。無断複製・不正使用等を禁じます。著作権法で認められている範囲内で、適切にご利用ください。

（課程博士関係）

学位論文の内容要旨

Stimulatory effect of imeglimin on incretin secretion
イメグリミンによるインクレチン分泌促進作用

神戸大学大学院医学研究科医科学専攻
糖尿病・内分泌内科学
（指導教員：小川 渉教授）
QUAN YINGYUE
権 映月

1

Introduction
Imeglimin is a newly launched anti-diabetic drug structurally related to metformin.
Despite the structural similarity, imeglimin augments glucose-stimulated insulin
secretion (GSIS), which the action metformin does not possess. The mechanism of how
imeglimin enhances GSIS remains ambiguous, however. Given that the incretins,
glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1), also enhance GSIS, we examined whether one of these hormones are involved in the
pharmacological actions of imeglimin.

Method
We examined plasma insulin and incretin levels during an oral glucose tolerance test
(OGTT) performed with C57BL/6JJcl (B6) and KK-Ay/TaJcl (KK-Ay) mice after a
single-dose of imeglimin alone or in combination with sitagliptin (a DPP-4 inhibitor).
We also investigated whether imeglimin had an additive effect on the enhancement of
GSIS by GIP or GLP-1 in mouse islets. The effect of the GLP-1 receptor antagonist
Exendin-9 on the glucose-lowering and insulin-stimulating actions of imeglimin has
also been examined. Moreover, the acute effects of imeglimin on blood glucose and
plasma insulin levels in Glp1r KO mice (GLP-1 receptor knockout mice on the C57BL/6

2

genetic background) was also involved in this study.

RESULTS
To provide insight into the mechanisms underlying the antidiabetic action of imeglimin,
we first investigated the acute effects of the imeglimin in B6 mice and KK-Ay mice.
OGTT was performed on both mice with a 6-h fasting and 1-h drug preloading. We
found that imeglimin decreased and increased blood glucose and plasma insulin levels,
respectively, in both mice, and increased plasma GIP and GLP-1 levels in KK-Ay mice
and GLP-1 levels in B6 mice.
Given that imeglimin was found to increase the plasma incretin concentration
in KK-Ay mice, we next investigated the effects of the combination of imeglimin and a
DPP-4 inhibitor sitagliptin on blood glucose and plasma insulin and incretin levels in
these mice. During the OGTT, the combination of the two drugs reduced blood glucose
levels to a significantly greater extent compared with either drug alone. The plasma
concentration of insulin tended to be higher in imeglimin-treated mice, whereas
sitagliptin had no substantial effect on insulin levels. However, combined treatment with
the two drugs markedly increased plasma insulin levels compared with treatment with
either drug alone. Plasma levels of GLP-1 tended to be increased in imeglimin-treated
mice and sitagliptin-treated mice, and they were significantly higher in mice treated

3

with both drugs than in those treated with either drug alone. These results indicated that
imeglimin and sitagliptin exerted synergistic effects on blood glucose, plasma insulin,
and plasma GLP-1 levels.
We next investigated the effects of imeglimin and incretins on GSIS in
pancreatic islets isolated from B6 mice. The results showed that imeglimin and GLP-1,
but not GIP, additively enhanced GSIS in islets of B6 mice.
We next examined whether the GLP-1 receptor antagonist exendin-9 might
influence the effects of imeglimin on blood glucose and plasma insulin levels during an
OGTT. We found that blood glucose levels were significantly lower in KK-Ay mice
treated with imeglimin, and this effect of imeglimin tended to be inhibited by exendin-9,
which suggested that exendin-9 might partially attenuate the glucose-lowering effect of
imeglimin. However, there was no difference between imeglimin alone and the
combination of the two drugs in terms of increasing plasma insulin levels during the
OGTT.
Finally, we investigated the effects of imeglimin on blood glucose and plasma
insulin levels during an OGTT in Glp1r KO mice. Imeglimin significantly attenuated
the increase in blood glucose levels in these mice to a similar extent as in B6 mice. The
plasma levels of insulin tended to be increased by imeglimin treatment. Whereas these

4

results do not exclude a possible contribution of GLP-1 to the glucose-lowering effect
of imeglimin, they implicate a mechanism independent of GLP-1.

DISCUSSION
We have shown that a single dose of imeglimin increased the plasma concentrations of
GIP and GLP-1 in KK-Ay mice during an OGTT, and the combination of imeglimin and
sitagliptin showed marked synergistic effects on the plasma levels of GLP-1 and insulin.
Moreover, imeglimin and GLP-1 enhanced GSIS by isolated mouse islets in an additive
manner. These results suggest that an imeglimin-induced increase in GLP-1 levels
contributes to the promotion of insulin secretion by this drug, with this effect of
imeglimin on GSIS being thought to play an important role in the antidiabetic action of
the drug.

In summary, we have here shown that imeglimin increases plasma GLP-1 levels in
mice, and that this action likely contributes at least in part to its stimulatory effect on
insulin secretion. Whereas further study is required to validate the clinical relevance of
this action of imeglimin, our current findings provide new insight into the
pharmacological effects and clinical use of this new antidiabetic drug.

神戸大学大学院医学（系）研究科（博士課程）
論 文 審 査 の 結 果 の 要 旨

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